Cocaine addiction is a serious public health issue that impacts the physical and emotional well-being and productivity of our society. It is a worldwide problem—Sofuoglu and Kosten (2006, Expert Opin. Emerging Drugs 11(1):91-98) estimate that there are 14 million cocaine users worldwide, two-thirds of which reside in the Americas (citing the 2005 World Drug Report published on line by the United Nations, Office on Drugs and Crimes). It has been estimated that as many as one in six individuals who use cocaine will become dependent on it (Hall and Carter, 2004, J. Med. Ethics 30:337-340, citing Anthony et al., 1994, Clin. Exper. Psychopharmacol. 2:244-268). Large doses of cocaine can provoke cardiac arrest, stroke, and seizure (Hall and Carter, supra, citing Vasica, 2002, Med. J. Austral. 177:260-262; Platt, 1977, Cocaine Addiction:theory, research and treatment, Harvard University Press, Cambridge, Mass.). Further, intravenous administration of cocaine carries the risk of infection by human immunodeficiency virus and various hepatitidies, including hepatitis B and C (Sofuoglu and Kosten, supra citing Booth et al., 2000, Drug Alcohol Dep. 58(3):219-226; Tyndall et al., 2003, Aids 17(6):887-893). Cocaine addiction has been linked to increased crime (Hall and Carter, supra, citing Anglin and Perrochet, 1998, Substance Use and Misure 33:1871-1914). Several years ago the societal cost of cocaine addiction in the United States alone was assessed to be $45 billion dollars, and a theoretical medication that decreased cocaine use by 10 percent was predicted to produce a $745 million dollar economic benefit (Sofuoglu and Kosten, supra citing Cartwright, 2000, Pharmacoeconomics 18(4):405-413).
To date, therapy for addiction has included detoxification and psychosocial treatment, but the relapse rate remains high (Hall and Carter, supra, citing Simpson et al., 1999, Arch. Gen. Psychiatry 56:507-514; Simpson et al., 2002, Arch. Gen. Psychiatry 59:538-544). New options for therapy that are being explored include pharmacologic agents such as dopamine agonists (e.g. disulfiram and amantadine); gamma amino butyric acid (“GABA”) enhancers such as tiagabine, baclofen, and topiramate; adrenergic blockers such as propranolol, labetalol, and carvediol; dopamine transport inhibitors such as GBR-12909 and RTI-336; and stimulants such as modafinil and amphetamines including NRP-104 (Sofuoglu and Kosten, supra). Such pharmacologic therapies, however, would generally require consistent compliance on the part of the subject.
As an alternative approach, efforts have been directed toward developing an anti-cocaine vaccine (Sofuoglu and Kosten, supra; Hall and Carter, supra, Montoya, 2008, NIH Public Access manuscript Addiciones, 20(2):111-115; Moreno and Janda, 2009, Pharmaol., Bioche, and Behavior 92:199-205). This approach is somewhat complicated by the fact that the cocaine molecule itself is too small to be immunogenic, and therefore, to be able to function as a vaccine, it must be attached to a larger carrier molecule—together with the carrier, the cocaine acts as a hapten.
Dr. Kim Janda and colleagues developed a potential cocaine vaccine by immunization of cocaine linked via a five carbon linker to Keyhole Limpet Hemocyanin (“KLH”), an immunogenic protein well known as a hapten carrier. Dr. Janda's group also reported the use of an anti-cocaine monoclonal antibody for passive immunization. See Carrera et al., 1995, Nature 378:727-730; Carrera et al., 2000, Proc. Natl. Acad. Sci. U.S.A. 97:6202-6206; Carrera et al., 2001, Proc. Natl. Acad. Sci. U.S.A. 98:1988-1992; Carrera et al., 2004, Bioorg. Med. Chem. 12:563-570; Carrera et al., Proc. Natl. Acad. Sci. U.S.A. 101:10416-10421; and Carrera et al., 2005, 81:709-714.
Dr. Thomas Kosten and his group have developed a potential cocaine vaccine in which succinylnorcocaine is linked to an immunogenic carrier protein derived from cholera B toxin (the “TA-CD” vaccine; Martell et al., 2005, Biol. Psychiatry 58(2):158-164). Clinical trials have shown that a vaccine containing the cholera toxin-cocaine conjugate, especially when administered as five inoculations over a three month period, produced a “robust and dose-related increase in anticocaine antibodies”; however, the antibody levels were observed to decline over time so that, about four months after the original series of inoculations, a booster inoculation is needed (Sofuoglu and Kosten, supra citing Hanet and Kosten, 2004, Expert Rev. Vaccines 3(1):11-18; Kantak et al., 2000, Psychopharmacol. 148(3):251-262; Kosten et al., 2002, Vaccine 20(7-8):1196-1204; Martell et al., 2005, Biol. Psychiatry 58(2):158-164; see also Orson et al., 2008, Ann. N.Y. Acad. Sci. 1141:257-269). Accordingly, because of the need for an initial series of injections and subsequent booster shots, this vaccine, like potential pharmaceutical therapies, requires a substantial level of commitment on the part of the subject.
As another example of a potential vaccine, Fox et al. (1996, Nature Medicine 2(10):1129-1132; Kantak et al., 2000, Psychopharmacol. 148:251-262) report that vaccination of mice with cocaine conjugated to immunogenic bovine serum albumin (“BSA”) produced a long-lasting antibody response. Mice immunized with cocaine-BSA were reported to exhibit altered cocaine pharmacokinetics. A monoclonal anti-cocaine antibody was generated which, when administered to rats, was observed to reduce self-administration of cocaine.
Hrafnkelsdottir et al. (2005, Biol. Pharm. Bull. 28(6):1038-1042) report induction of protective and specific antibodies against cocaine in mice immunized with an intranasal cocaine vaccine containing cocaine conjugated to KLH and the mucosal adjuvant, macrogol-6-glycerol capylocaprate (“RhinoVax”). Nasal administration was observed to confer a beneficial mucosal immunity.
Disadvantages of these vaccine approaches include (i) use of an immunogenic carrier protein would result in an undesirable extraneous immune response to the carrier itself, (ii) use of long tethers to link a hapten to a carrier protein could result in formation of a number of neo-epitopes which, in turn, could “dilute” the specific immune response to a hapten, and (iii) maintenance of antibody levels would require the administration of periodic booster vaccinations.
Deng et al., 2002, Proc. Natl. Acad. Sci. U.S.A. 99(6):3412-3416 showed that cocaine covalently modifies plasma proteins in vivo forming a benzoyl ecgonine (“BE”) amide hapten through lysine ε-amino groups of plasma proteins such as albumin (see FIG. 1). They showed the presence of such cocaine conjugates in plasma of rats and human subjects chronically exposed to cocaine. Further, it was found that when the benzoyl ecgonine N-hydroxysuccinimide ester of cocaine was administered directly to mice, plasma proteins were conjugated to cocaine in vivo and mice developed anti-cocaine antibodies, indicating that the proteins conjugated in vivo were immunogenic. Deng et al. also showed that anti-cocaine antibodies were detected in some long-term cocaine users.
Various other publications and patents that relate to anti-drug vaccines and antibodies include U.S. Pat. No. 6,699,474 (drug conjugated to carrier such as KLH); Kinsey et al., 2009, Immunology and Cell Biology 87: 309-314 (review of anti-drug vaccines); U.S. Pat. Nos. 7,452,541 and 6,932,971 (hapten conjugated to protein carrier in a repetitive array); Hardin et al, 1998, J Pharmacol Exp Ther 285:1113-1122 and Proksch et al., 2000, J. Pharmacol Exp Ther. 292:831-837(antibodies toward phencyclidine (PCP) reduce PCP levels in the brain); Byrnes-Blake et al., 2001, Int Immunopharmacol 1:329-338 (antibodies to methamphetamine); U.S. Pat. No. 5,256,409 (vaccine comprising a carrier protein bound to one hapten from the desipramine/imipramine class and another hapten from the nortriptyline/amitriptyline class of drugs); Carrera et al., 1995, Nature 379:727-730; WO 92/03163; U.S. Pat. No. 6,383,490 (anti-cocaine antibodies; cocaine/carrier conjugates; importance of linker in joining cocaine to carrier); Landry et al., 1993, Science 259:1899-1901 and WO 93/20076 (immunization with transition state analogues of cocaine to produce catalytic antibodies that inactivate cocaine); Spector, et al., 1973, Pharmacol. Rev. 25:281-291 and Berkowitz et al., 1982, Science 178:1290-1292 (anti-morphine antibodies); Bagasra, et al., 1992, Immunopharmacol. 23:173-179 and Gallacher, 1994, Immunopharmacol 27:79-81 (cocaine/carrier conjugates; anti-cocaine antibodies); Killian et al., 1978, Pharmacol. Biochem. Behavior 9:347-352 and Pentel et al., 1991, Drug Met. Dispositions 19:24-28 (passive immunization against drugs); EP 0 613 899 A2 (cocaine/protein conjugate; anti-cocaine antibodies); U.S. Pat. Nos. 3,888,866 and 4,123,431 (cocaine/protein conjugates; anti-cocaine antibodies); WO 93/12111 (cocaine/protein conjugates); U.S. Pat. Nos. 4,620,977, 4,813,924, 4,834,973; and 5,037,645 (drug/protein conjugates); and U.S. Pat. No. 6,054,127 (drug/carrier conjugates where carrier is immunogenic; cocaine/carrier conjugates).